Pyridineamine derivatives

ABSTRACT

This invention relates to novel compounds that are pyrimidineamine derivatives and pharmaceutically acceptable salts thereof. More specifically, this invention relates to novel pyrimidineamine derivatives that are derivatives of pazopanib. This invention also provides compositions comprising one or more compound of this invention and a carrier, and the use of the disclosed compounds and compositions in methods of treating diseases and conditions that are beneficially treated by administering a VEGFR (1-3) inhibitor, such as pazopanib.

CROSS-REFERENCE TO PRIOR APPLICATION

This application claims priority under 35 USC 119 to U.S. ProvisionalApplication Ser. No. 61/194,351, filed Sep. 26, 2008, the entiredisclosure of which is hereby incorporated by reference.

BACKGROUND OF THE INVENTION

Pazopanib, also known as5-[4-[N-(2,3-Dimethyl-2H-indazol-6-yl)-N-methylamino]pyrimidin-2-ylamino]-2-methylbenzenesulfonamidehydrochloride, inhibits the VEGF (vascular epidermal growth factor)-1(Flt-1) receptor, the VEGF-2 (FLK-1/KDR) receptor, and the VEGF-3(Flt-4) receptor, thus blocking angiogenesis and tumor growth.

Pazopanib is currently in clinical trials for renal cell carcinoma,breast cancer, cervical cancer, non-small cell lung cancer, ovariancancer, fallopian tube cancer, peritoneal cancer, prostate cancer,rhinopharyngeal cancer, solid tumor cancer, bladder cancer, urethralcancer, multiforme glioblastoma, malignant glioma, pleural mesothelioma,multiple myeloma, neuroendocrine cancer, sarcoma, colorectal cancer,liver cancer, macular degeneration and psoriasis.

The most common adverse events were nausea, diarrhea, fatigue,hypertension, anorexia, vomiting, and hair depigmentation (Sorbera, L etal, Drugs Fut, 2006, 31(7): 585).

Despite the beneficial activities of pazopanib, there is a continuingneed for new compounds to treat the aforementioned diseases andconditions.

SUMMARY OF THE INVENTION

This invention relates to novel compounds that are pyrimidineaminederivatives and pharmaceutically acceptable salts thereof. Morespecifically, this invention relates to novel pyrimidineaminederivatives that are derivatives of pazopanib. This invention alsoprovides compositions comprising one or more compound of this inventionand a carrier, and the use of the disclosed compounds and compositionsin methods of treating diseases and conditions that are beneficiallytreated by administering a VEGFR (1-3) inhibitor, such as pazopanib.

DETAILED DESCRIPTION OF THE INVENTION

The term “treat” means one or more of decrease, suppress, attenuate,diminish, arrest, or stabilize the development or progression of adisease (e.g., a disease or disorder delineated herein).

“Disease” means any condition or disorder that damages or interfereswith the normal function of a cell, tissue, or organ.

It will be recognized that some variation of natural isotopic abundanceoccurs in a synthesized compound depending upon the origin of chemicalmaterials used in the synthesis. Thus, a preparation of pazopanib willinherently contain small amounts of deuterated isotopologues. Theconcentration of naturally abundant stable hydrogen and carbon isotopes.notwithstanding this variation, is small and immaterial as compared tothe degree of stable isotopic substitution of compounds of thisinvention. See, for instance, Wada E et al, Seikagaku 1994, 66:15;Gannes L Z et al, Comp Biochem Physiol Mol Integr Physiol 1998, 119:725.In a compound of this invention, when a particular position isdesignated as having deuterium, it is understood that the abundance ofdeuterium at that position is at least 3340 times greater than thenatural abundance of deuterium, which is 0.015% (i.e., at least 50.1%incorporation of deuterium).

The term “isotopic enrichment factor” as used herein means the ratiobetween the isotopic abundance and the natural abundance of a specifiedisotope.

In other embodiments, a compound of this invention has an isotopicenrichment factor for each designated deuterium atom of at least 3500(52.5% deuterium incorporation at each designated deuterium atom), atleast 4000 (60% deuterium incorporation), at least 4500 (67.5% deuteriumincorporation), at least 5000 (75% deuterium), at least 5500 (82.5%deuterium incorporation), at least 6000 (90% deuterium incorporation),at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97%deuterium incorporation), at least 6600 (99% deuterium incorporation),or at least 6633.3 (99.5% deuterium incorporation).

In the compounds of this invention any atom not specifically designatedas a particular isotope is meant to represent any stable isotope of thatatom. Unless otherwise stated, when a position is designatedspecifically as “H” or “hydrogen”, the position is understood to havehydrogen at its natural abundance isotopic composition.

The term “isotopologue” refers to a species that differs from a specificcompound of this invention only in the isotopic composition thereof.

The term “compound,” when referring to a compound of this invention,refers to a collection of molecules having an identical chemicalstructure, except that there may be isotopic variation among theconstituent atoms of the molecules. Thus, it will be clear to those ofskill in the art that a compound represented by a particular chemicalstructure containing indicated deuterium atoms, will also contain lesseramounts of isotopologues having hydrogen atoms at one or more of thedesignated deuterium positions in that structure. The relative amount ofsuch isotopologues in a compound of this invention will depend upon anumber of factors including the isotopic purity of deuterated reagentsused to make the compound and the efficiency of incorporation ofdeuterium in the various synthesis steps used to prepare the compound.However, as set forth above the relative amount of such isotopologues intoto will be less than 49.9% of the compound.

The invention also provides salts of the compounds of the invention.

A salt of a compound of this invention is formed between an acid and abasic group of the compound, such as an amino functional group, or abase and an acidic group of the compound, such as a carboxyl functionalgroup. According to another embodiment, the compound is apharmaceutically acceptable acid addition salt.

The term “pharmaceutically acceptable,” as used herein, refers to acomponent that is, within the scope of sound medical judgment, suitablefor use in contact with the tissues of humans and other mammals withoutundue toxicity, irritation, allergic response and the like, and arecommensurate with a reasonable benefit/risk ratio. A “pharmaceuticallyacceptable salt” means any non-toxic salt that, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound of this invention. A “pharmaceutically acceptable counterion”is an ionic portion of a salt that is not toxic when released from thesalt upon administration to a recipient.

Acids commonly employed to form pharmaceutically acceptable saltsinclude inorganic acids such as hydrogen bisulfide, hydrochloric acid,hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, aswell as organic acids such as para-toluenesulfonic acid, salicylic acid,tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylicacid, fumaric acid, gluconic acid, glucuronic acid, formic acid,glutamic acid, methanesulfonic acid, ethanesulfonic acid,benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonicacid, carbonic acid, succinic acid, citric acid, benzoic acid and aceticacid, as well as related inorganic and organic acids. Suchpharmaceutically acceptable salts thus include sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, propionate, decanoate, caprylate, acrylate, formate,isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate,succinate, suberate, sebacate, fumarate, malcate, butyne-1,4-dioate,hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate,terephthalate, sulfonate, xylene sulfonate, phenylacetate,phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate,glycolate, maleate, tartrate, methanesulfonate, propanesulfonate,naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and othersalts. In one embodiment, pharmaceutically acceptable acid additionsalts include those formed with mineral acids such as hydrochloric acidand hydrobromic acid, and especially those formed with organic acidssuch as maleic acid.

The compounds of the present invention (e.g., compounds of Formula I),may contain an asymmetric carbon atom, for example, as the result ofdeuterium substitution or otherwise. As such, compounds of thisinvention can exist as either individual enantiomers, or mixtures of thetwo enantiomers. Accordingly, a compound of the present invention mayexist as either a racemic mixture or a scalemic mixture, or asindividual respective stereoisomers that are substantially free fromanother possible stereoisomer. The term “substantially free of otherstereoisomers” as used herein means less than 25% of otherstereoisomers, preferably less than 10% of other stereoisomers, morepreferably less than 5% of other stereoisomers and most preferably lessthan 2% of other stereoisomers, or less than “X”% of other stereoisomers(wherein X is a number between 0 and 100, inclusive) are present.Methods of obtaining or synthesizing an individual enantiomer for agiven compound are known in the art and may be applied as practicable tofinal compounds or to starting material or intermediates.

Unless otherwise indicated, when a disclosed compound is named ordepicted by a structure without specifying the stereochemistry and hasone or more chiral centers, it is understood to represent all possiblestereoisomers of the compound.

The term “stable compounds,” as used herein, refers to compounds whichpossess stability sufficient to allow for their manufacture and whichmaintain the integrity of the compound for a sufficient period of timeto be useful for the purposes detailed herein (e.g., formulation intotherapeutic products, intermediates for use in production of therapeuticcompounds, isolatable or storable intermediate compounds, treating adisease or condition responsive to therapeutic agents).

“D” refers to deuterium. “Stereoisomer” refers to both enantiomers anddiastereomers. “Tert”, “^(t)”, and “t−” each refer to tertiary. “US”refers to the United States of America.

Throughout this specification, a variable may be referred to generally(e.g., “each R”) or may be referred to specifically (e.g., R¹, R², R³,etc.). Unless otherwise indicated, when a variable is referred togenerally, it is meant to include all specific embodiments of thatparticular variable.

Therapeutic Compounds

The present invention provides a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

each Y is independently selected from hydrogen and deuterium;

each R is independently selected from CH₃, CH₂D, CHD₂ and CD₃; and

when each R is CH₃, at least one Y is deuterium.

One embodiment of this invention provides a compound of Formula I whereeach R is independently selected from CH₃ and CD₃.

Another embodiment provides a compound of Formula I where R¹ is CD₃. Inone aspect of this embodiment, each of R²-R⁴ is independently selectedfrom CH₃ and CD₃.

Another embodiment provides a compound where Y¹, Y² and Y³ are the same.In one aspect of this embodiment, each R is independently selected fromCH₃ and CD₃. In another aspect, R¹ is CD₃ and each of R²-R⁴ isindependently selected from CH₃ and CD₃. In another aspect of thisembodiment, Y¹, Y² and Y³ are all deuterium. In yet another aspect, Y¹,Y² and Y³ are all hydrogen.

Another embodiment provides a compound where Y⁶, Y⁷ and Y⁸ are the same.In one aspect of this embodiment, each R is independently selected fromCH₃ and CD₃. In another aspect R¹ is CD₃ and each R²-R⁴ is independentlyselected from CH₃ and CD₃. In yet another aspect Y¹, Y² and Y³ are thesame. In a particular aspect, Y¹, Y² and Y³ are all the same and each Ris independently selected from CH₃ and CD₃. In yet another aspect, Y¹,Y² and Y³ are the same, R¹ is CD₃ and each of R²-R⁴ is independentlyselected from CH₃ and CD₃. In another aspect, Y⁶, Y⁷ and Y³ are alldeuterium. In another aspect, Y⁶, Y⁷ and Y⁸ are all hydrogen. In anotheraspect, R² is CD₃. In another aspect, R³ is CD₃. In another aspect, R²and R³ are both CD₃.

Another embodiment provides a compound where Y⁵ is deuterium. In oneaspect of this embodiment, each R is independently selected from CH₃ andCD₃. In another aspect, R¹ is CD₃ and each R²-R⁴ is independentlyselected from CH₃ and CD₃. In yet another aspect, Y¹, Y² and Y³ are thesame. In a further aspect Y¹, Y² and Y³ are the same and each K isindependently selected from CH₃ and CD₃. In another aspect, Y⁶, Y⁷ andY⁸ are the same and each R is independently selected from CH₃ and CD₃.In another aspect, Y⁶, Y⁷ and Y⁸ are the same, R¹ is CD₃ and each R²-R⁴is independently selected from CH₃ and CD₃. In yet another aspect, Y¹,Y² and Y³ are the same and Y⁶, Y⁷ and Y⁸ are the same. In anotheraspect, Y¹, Y² and Y³ are the same, Y⁶, Y⁷ and Y⁸ are the same R³ is CD₃and each of R₂-R₄ is independently selected from CH₃ and CD₃. In anotheraspect of this embodiment, Y⁴ is deuterium.

In another embodiment, Y¹, Y² and Y³ are deuterium and R¹ is CD₃. In oneaspect of this embodiment, each of R²-R⁴ is independently selected fromCH₃ and CD₃. In another aspect, Y⁶, Y⁷ and Y⁸ are the same. In yetanother aspect, Y⁶, Y⁷ and Y⁸ are the same and each R²-R⁴ isindependently selected from CH₃ and CD₃.

Yet another embodiment provides a compound where R⁴ is CD₃.

Another embodiment provides a compound where R⁴ is CH₃.

Compounds of Formula I are comprised of three rings: a phenyl ring, apyrimidine ring and an indazole ring, embodiments of which are describedabove. It will be apparent to one skilled in the art that features of aparticular ring may be combined with features of one or more other ringsto provide other embodiments of this invention.

Examples of specific compounds of Formula I are set forth in Table 1below.

TABLE 1 Examples of Specific Compounds of Formula I Compound Y¹ R¹ Y² Y³Y⁴ Y⁵ Y⁶ Y⁷ R² R³ Y⁸ R⁴ 100 D CD₃ D D D D D D CD₃ CD₃ D CD₃ 101 H CD₃ HH D D D D CD₃ CD₃ D CD₃ 102 D CD₃ D D H D D D CD₃ CD₃ D CD₃ 103 D CD₃ DD D H D D CD₃ CD₃ D CD₃ 104 D CD₃ D D H H D D CD₃ CD₃ D CD₃ 105 D CD₃ DD D D H H CD₃ CD₃ H CD₃ 106 H CD₃ H H H H H H CD₃ CD₃ H CD₃ 107 H CH₃ HH H H H H CH₃ CD₃ H CD₃ 108 H CH₃ H H H H H H CH₃ CH₃ H CD₃ 109 H CH₃ HH H H H H CH₃ CD₃ H CH₃ 110 H CH₃ H H H H H H CD₃ CD₃ H CD₃ 111 H CD₃ HH H H H H CH₃ CD₃ H CD₃

In another set of embodiments, any atom not designated as deuterium inany of the embodiments set forth above is present at its naturalisotopic abundance.

The synthesis of compounds of Formula I can be readily achieved bysynthetic chemists of ordinary skill. Relevant procedures andintermediates are disclosed, for instance in Sorbera, L et al, DrugsFut, 2006, 31(7):585; and PCT patent publications WO2006020564,WO2003106416 and WO2002059110.

Such methods can be carried out utilizing corresponding deuterated andoptionally, other isotope-containing reagents and/or intermediates tosynthesize the compounds delineated herein, or invoking standardsynthetic protocols known in the art for introducing isotopic atoms to achemical structure. Certain intermediates can be used with or withoutpurification (e.g., filtration, distillation, sublimation,crystallization, trituration, solid phase extraction, andchromatography).

Exemplary Synthesis

The schemes shown below illustrate how compounds of Formula I may beprepared.

Scheme 1 shows a general route to preparing compounds of Formula I. Anappropriately-deuterated aniline 10 is treated with tert-butyl nitritein acetic acid to afford cyclized indazole 11. Alkylation withappropriately-deuterated dimethylsulfate provides heterocycle 12.Reduction of the nitro group with tin chloride and HCl yields amine 13.Reaction of amine 13 with appropriately-deuterated dichloropyrimidine 14provides adduct 15. Alkylation of the secondary amine withappropriately-deuterated methyl iodide yields compound 16, and reactionwith appropriately-deuterated aniline 17 in the presence of HCl affordsdesired Formula I compound as the HCl salt.

Known 5-deutero-2,4-dichloropyrimidine,

(Ple, N et al, Tet Lett 1993, 34(10):1605-8.) may be used in Scheme 1 asintermediate 14 to provide a compound of Formula I wherein Y⁴ ishydrogen and Y⁵ is deuterium.

Scheme 2 shows a route to making the deuterated anilines 10, which areuseful starting materials for Scheme 1. An appropriately-deuteratedethylbenzene 20 is treated with Bu₄NNO₃ and tritluoroacetic anhydride toprovide nitrobenzene 21 according to the general procedure of Masci, B,Tetrahedron 1989, 45(9):2719-30. Hydrogenation of the nitro groupaffords aniline 22, following the general procedure of Klyuev, M V etal, Neftekhimiya 2002, 42(1):32-35. Treatment of aniline 22 with KNO₃and H₂SO₄ via the method of Ruiz-Caro J, et al, Bioorg Med Chem Lett2006, 16(3):668-671 affords the desired aniline 10.

Commercially-available ethylbenzene-d₁₀ may be used in Scheme 2 asstarting compound 20 to ultimately produce a compound of Formula Iwherein Y⁶, Y⁷ and Y⁸ are deuterium, and R² is CD₃.

Scheme 3 shows the preparation of deuterated sulfonamide 17 that is usedin Scheme 1. An appropriately-deuterated nitrotoluene 30 is treated withchlorosulfonic acid, followed by ammonium hydroxide, to providesulfonamide 31 according to the procedure of Chinese patent publicationCN1869015A or that of Srikanth, K et al, Bioorg Med Chem 2002,10(6):1841-1854. Reduction of the nitro group with either hydrogen andpalladium (see Chinese patent publication CN1702064A) or iron andammonium chloride (sec Rockway, T W et al, Bioorg Med Chem Lett 2006,16(14):3833-3838) yields desired sulfonamide 17.

Commercially-available p-nitrotoluene-α, α, α-d₃,

may be used in Scheme 3 as compound 30 to provide intermediate 17 andsubsequently a compound of Formula I wherein R¹ is CD₃; and Y¹, Y² andY³ are simultaneously hydrogen.

Alternatively, p-nitrotoluene-d₇ (see Gorissen, II et al Editor(s):Pleiss, Ulrich; Voges, Rolf. Synthesis and Applications of IsotopicallyLabelled Compounds, Proceedings of the International Symposium, 7th,Dresden, Germany, Jun. 18-22, 2000 (2001), Meeting Date 2000, 170-173;or Delgado, M et al, J Am Chem Soc 1986, 108(14):4135-8) may be used inScheme 3 as compound 30 to provide intermediate 17 and a compound ofFormula I wherein R¹ is CD₃ and Y¹, Y² and Y³ are simultaneouslydeuterium.

The specific approaches and compounds shown above are not intended to belimiting. The chemical structures in the schemes herein depict variablesthat are hereby defined commensurately with chemical group definitions(moieties, atoms, etc.) of the corresponding position in the compoundformulae herein, whether identified by the same variable name (i.e., R¹,R², R³, etc.) or not. The suitability of a chemical group in a compoundstructure for use in the synthesis of another compound is within theknowledge of one of ordinary skill in the art. Additional methods ofsynthesizing compounds of Formula I and their synthetic precursors,including those within routes not explicitly shown in schemes herein,are within the means of chemists of ordinary skill in the art. Methodsfor optimizing reaction conditions and, if necessary, minimizingcompeting by-products, are known in the art.

Synthetic chemistry transformations and protecting group methodologies(protection and deprotection) useful in synthesizing the applicablecompounds are known in the art and include, for example, those describedin Larock R, Comprehensive Organic Transformations, VCH Publishers(1989); Greene T W et al, Protective Groups in Organic Synthesis, 3^(rd)Ed., John Wiley and Sons (1999); Fieser Let al, Fieser and Fieser'sReagents for Organic Synthesis, John Wiley and Sons (1994); and PaquetteL, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley andSons (1995) and subsequent editions thereof.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds.

Compositions

The invention also provides pyrogen-free compositions comprising aneffective amount of a compound of Formula I (e.g., including any of theformulae herein), or a pharmaceutically acceptable salt of saidcompound; and an acceptable carrier. Preferably, a composition of thisinvention is formulated for pharmaceutical use (“a pharmaceuticalcomposition”), wherein the carrier is a pharmaceutically acceptablecarrier. The carrier(s) are “acceptable” in the sense of beingcompatible with the other ingredients of the formulation and, in thecase of a pharmaceutically acceptable carrier, not deleterious to therecipient thereof in an amount used in the medicament.

Pharmaceutically acceptable carriers, adjuvants and vehicles that may beused in the pharmaceutical compositions of this invention include, butare not limited to, ion exchangers, alumina, aluminum stearate,lecithin, serum proteins, such as human serum albumin, buffer substancessuch as phosphates, glycine, sorbic acid, potassium sorbate, partialglyceride mixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium tri silicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

If required, the solubility and bioavailability of the compounds of thepresent invention in pharmaceutical compositions may be enhanced bymethods well-known in the art. One method includes the use of lipidexcipients in the formulation. See “Oral Lipid-Based Formulations:Enhancing the Bioavailability of Poorly Water-Soluble Drugs (Drugs andthe Pharmaceutical Sciences),” David J. Hauss, ed. Informa Healthcare,2007; and “Role of Lipid Excipients in Modifying Oral and ParenteralDrug Delivery: Basic Principles and Biological Examples.”Kishor M.Wasan, ed. Wiley-Interscience, 2006.

Another known method of enhancing bioavailability is the use of anamorphous form of a compound of this invention optionally formulatedwith a poloxamer, such as LUTROL™ and PLURONIC™ (BASF Corporation), orblock copolymers of ethylene oxide and propylene oxide. See U.S. Pat.No. 7,014,866; and United States patent publications 20060094744 and20060079502.

The pharmaceutical compositions of the invention include those suitablefor oral, rectal, nasal, topical (including buccal and sublingual),vaginal or parenteral (including subcutaneous, intramuscular,intravenous and intradermal) administration. In certain embodiments, thecompound of the formulae herein is administered transdermally (e.g.,using a transdermal patch or iontophoretic techniques). Otherformulations may conveniently be presented in unit dosage form, e.g.,tablets, sustained release capsules, and in liposomes, and may beprepared by any methods well known in the art of pharmacy. See, forexample, Remington: The Science and Practice of Pharmacy, LippincottWilliams & Wilkins, Baltimore, Md. (20th ed. 2000).

Such preparative methods include the step of bringing into associationwith the molecule to be administered ingredients such as the carrierthat constitutes one or more accessory ingredients. In general, thecompositions are prepared by uniformly and intimately bringing intoassociation the active ingredients with liquid carriers, liposomes orfinely divided solid carriers, or both, and then, if necessary, shapingthe product.

In certain embodiments, the compound is administered orally.Compositions of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, sachets, or tabletseach containing a predetermined amount of the active ingredient; apowder or granules; a solution or a suspension in an aqueous liquid or anon-aqueous liquid: an oil-in-water liquid emulsion; a water-in-oilliquid emulsion; packed in liposomes; or as a bolus, etc. Soft gelatincapsules can be useful for containing such suspensions, which maybeneficially increase the rate of compound absorption.

In the case of tablets for oral use, carriers that are commonly usedinclude lactose and corn starch. Lubricating agents, such as magnesiumstearate, are also typically added. For oral administration in a capsuleform, useful diluents include lactose and dried cornstarch. When aqueoussuspensions are administered orally, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweeteningand/or flavoring and/or coloring agents may be added.

Compositions suitable for oral administration include lozengescomprising the ingredients in a flavored basis, usually sucrose andacacia or tragacanth; and pastilles comprising the active ingredient inan inert basis such as gelatin and glycerin, or sucrose and acacia.

Compositions suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents. The formulations may be presented in unit-dose or multi-dosecontainers, for example, sealed ampules and vials, and may be stored ina freeze dried (lyophilized) condition requiring only the addition ofthe sterile liquid carrier, for example water for injections,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tablets.

Such injection solutions may be in the form, for example, of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to techniques known in the art using suitabledispersing or wetting agents (such as, for example, Tween 80) andsuspending agents. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example, as a solutionin 1,3-butanediol. Among the acceptable vehicles and solvents that maybe employed are mannitol, water, Ringer's solution and isotonic sodiumchloride solution. In addition, sterile, Fixed oils are conventionallyemployed as a solvent or suspending medium. For this purpose, any blandfixed oil may be employed including synthetic mono- or diglycerides.Fatty acids, such as oleic acid and its glyceride derivatives are usefulin the preparation of injectables, as are naturalpharmaceutically-acceptable oils, such as olive oil or castor oil,especially in their polyoxyethylated versions. These oil solutions orsuspensions may also contain a long-chain alcohol diluent or dispersant.

The pharmaceutical compositions of this invention may be administered inthe form of suppositories for rectal administration. These compositionscan be prepared by mixing a compound of this invention with a suitablenon-irritating excipient which is solid at room temperature but liquidat the rectal temperature and therefore will melt in the rectum torelease the active components. Such materials include, but are notlimited to, cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of this invention may be administered bynasal aerosol or inhalation. Such compositions are prepared according totechniques well-known in the art of pharmaceutical formulation and maybe prepared as solutions in saline, employing benzyl alcohol or othersuitable preservatives, absorption promoters to enhance bioavailability,fluorocarbons, and/or other solubilizing or dispersing agents known inthe art. See, e.g.: Rabinowitz JD and Zaffaroni AC, U.S. Pat. No.6,803,031, assigned to Alexza Molecular Delivery Corporation.

Topical administration of the pharmaceutical compositions of thisinvention is especially useful when the desired treatment involves areasor organs readily accessible by topical application. For topicalapplication topically to the skin, the pharmaceutical composition shouldbe formulated with a suitable ointment containing the active componentssuspended or dissolved in a carrier. Carriers for topical administrationof the compounds of this invention include, but are not limited to,mineral oil, liquid petroleum, white petroleum, propylene glycol,polyoxyethylene polyoxypropylene compound, emulsifying wax, and water.Alternatively, the pharmaceutical composition can be formulated with asuitable lotion or cream containing the active compound suspended ordissolved in a carrier. Suitable carriers include, but are not limitedto, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esterswax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. Thepharmaceutical compositions of this invention may also be topicallyapplied to the lower intestinal tract by rectal suppository formulationor in a suitable enema formulation. Topically-transdermal patches andiontophoretic administration are also included in this invention.

Application of the subject therapeutics may be local, so as to beadministered at the site of interest. Various techniques can be used forproviding the subject compositions at the site of interest, such asinjection, use of catheters, trocars, projectiles, pluronic gel, stents,sustained drug release polymers or other device which provides forinternal access.

Thus, according to yet another embodiment, the compounds of thisinvention may be incorporated into compositions for coating animplantable medical device, such as prostheses, artificial valves,vascular grafts, stents, or catheters. Suitable coatings and the generalpreparation of coated implantable devices are known in the art and areexemplified in U.S. Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. Thecoatings are typically biocompatible polymeric materials such as ahydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethyleneglycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof.The coatings may optionally be further covered by a suitable topcoat offluorosilicone, polysaccharides, polyethylene glycol, phospholipids orcombinations thereof to impart controlled release characteristics in thecomposition. Coatings for invasive devices are to be included within thedefinition of pharmaceutically acceptable carrier, adjuvant or vehicle,as those terms are used herein.

According to another embodiment, the invention provides a method ofcoating an implantable medical device comprising the step of contactingsaid device with the coating composition described above. It will beobvious to those skilled in the art that the coating of the device willoccur prior to implantation into a mammal.

According to another embodiment, the invention provides a method ofimpregnating an implantable drug release device comprising the step ofcontacting said drug release device with a compound or composition ofthis invention. Implantable drug release devices include, but are notlimited to, biodegradable polymer capsules or bullets, non-degradable,diffusible polymer capsules and biodegradable polymer wafers.

According to another embodiment, the invention provides an implantablemedical device coated with a compound or a composition comprising acompound of this invention, such that said compound is therapeuticallyactive.

According to another embodiment, the invention provides an implantabledrug release device impregnated with or containing a compound or acomposition comprising a compound of this invention, such that saidcompound is released from said device and is therapeutically active.

Where an organ or tissue is accessible because of removal from thepatient, such organ or tissue may be bathed in a medium containing acomposition of this invention, a composition of this invention may bepainted onto the organ, or a composition of this invention may beapplied in any other convenient way.

In another embodiment, a composition of this invention further comprisesa second therapeutic agent. The second therapeutic agent may be selectedfrom any compound or therapeutic agent known to have or thatdemonstrates advantageous properties when administered with a compoundhaving the same mechanism of action as pazopanib.

Preferably, the second therapeutic agent is an agent useful in thetreatment or prevention of a disease or condition selected from cancerincluding renal cell carcinoma, breast cancer, cervical cancer,non-small cell lung cancer, ovarian cancer, fallopian tube cancer,peritoneal cancer, prostate cancer, rhinopharyngeal cancer, solid tumorcancer, bladder cancer, urethral cancer, multiforme glioblastoma,malignant glioma, pleural mesothelioma, multiple myeloma, neuroendocrinecancer, sarcoma, colorectal cancer, and liver cancer; ocular neovasculardisorders including macular degeneration, angioid streaks, uveitis andmacular edema; and psoriasis.

In one embodiment, the second therapeutic agent is selected fromlapatinib, FOLFOX6 (fluorouracil, oxaliplatin, leucovorin). CapeOx(capecitabine, oxaliplatin), paclitaxel, and carboplatin.

In another embodiment, the invention provides separate dosage forms of acompound of this invention and one or more of any of the above-describedsecond therapeutic agents, wherein the compound and second therapeuticagent are associated with one another. The term “associated with oneanother” as used herein means that the separate dosage forms arepackaged together or otherwise attached to one another such that it isreadily apparent that the separate dosage forms are intended to be soldand administered together (within less than 24 hours of one another,consecutively or simultaneously).

In the pharmaceutical compositions of the invention, the compound of thepresent invention is present in an effective amount. As used herein, theterm “effective amount” refers to an amount which, when administered ina proper dosing regimen, is sufficient to treat (therapeutically orprophylactically) the target disorder. For example, and effective amountis sufficient to reduce or ameliorate the severity, duration orprogression of the disorder being treated, prevent the advancement ofthe disorder being treated, cause the regression of the disorder beingtreated, or enhance or improve the prophylactic or therapeutic effect(s)of another therapy.

The interrelationship of dosages for animals and humans (based onmilligrams per meter squared of body surface) is described in Freireichet al, (1966) Cancer Chemother. Rep 50: 219. Body surface area may beapproximately determined from height and weight of the patient. See,e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y., 1970,537.

In one embodiment, an effective amount of a compound of this inventioncan range from about 2 to 8000 mg per treatment. In more specificembodiments the range is from about 20 to 4000 mg, or from 40 to 1600mg, or most specifically from 200 to 800 mg. Treatment typically isadministered one to two times daily.

Effective doses will also vary, as recognized by those skilled in theart, depending on the diseases treated, the severity of the disease, theroute of administration, the sex, age and general health condition ofthe patient, excipient usage, the possibility of co-usage with othertherapeutic treatments such as use of other agents and the judgment ofthe treating physician. For example, guidance for selecting an effectivedose can be determined by reference to the prescribing information forpazopanib.

For pharmaceutical compositions that comprise a second therapeuticagent, an effective amount of the second therapeutic agent is betweenabout 20% and 100% of the dosage normally utilized in a monotherapyregime using just that agent. Preferably, an effective amount is betweenabout 70% and 100% of the normal monotherapeutic dose. The normalmonotherapeutic dosages of these second therapeutic agents are wellknown in the art. See, e.g., Wells et al, eds., PharmacotherapyHandbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDRPharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition,Tarascon Publishing, Loma Linda, Calif. (2000), each of which referencesare incorporated herein by reference in their entirety.

It is expected that some of the second therapeutic agents referencedabove will act synergistically with the compounds of this invention.When this occurs, it will allow the effective dosage of the secondtherapeutic agent and/or the compound of this invention to be reducedfrom that required in a monotherapy. This has the advantage ofminimizing toxic side effects of either the second therapeutic agent ofa compound of this invention, synergistic improvements in efficacy,improved ease of administration or use and/or reduced overall expense ofcompound preparation or formulation.

Methods of Treatment

In another embodiment, the invention provides a method of inhibiting theactivity of the VEGF (1-3) receptors in a cell, comprising contacting acell with one or more compounds of Formula I herein.

According to another embodiment, the invention provides a method oftreating a disease that is beneficially treated by pazopanib in apatient in need thereof comprising the step of administering to saidpatient an effective amount of a compound of Formula I orpharmaceutically acceptable salt thereof or a composition of thisinvention. Such diseases are well known in the art and are disclosed in,but not limited to the following patents and published applications: WO2002059110, WO 2006020564, WO 2007064752, and WO 2007064753. Suchdiseases include, but are not limited to, cancer including renal cellcarcinoma, breast cancer, cervical cancer, non-small cell lung cancer,ovarian cancer, fallopian tube cancer, peritoneal cancer, prostatecancer, rhinopharyngeal cancer, solid tumor cancer, bladder cancer,urethral cancer, multi forme glioblastoma, malignant glioma, pleuralmesothelioma, multiple myeloma, neuroendocrine cancer, sarcoma,colorectal cancer, and liver cancer; ocular neovascular disordersincluding macular degeneration, angiod streaks, uveitis and macularedema; and psoriasis.

In one particular embodiment, the method of this invention is used totreat a disease or condition selected from renal cell carcinoma, breastcancer, cervical cancer, non-small cell lung cancer, ovarian cancer,fallopian tube cancer, peritoneal cancer, prostate cancer,rhinopharyngeal cancer, solid tumor cancer, bladder cancer, urethralcancer, multiforme glioblastoma, malignant glioma, pleural mesothelioma,multiple myeloma, neuroendocrine cancer, sarcoma, colorectal cancer,liver cancer, macular degeneration and psoriasis.

Methods delineated herein also include those wherein the patient isidentified as in need of a particular stated treatment. Identifying apatient in need of such treatment can be in the judgment of a patient ora health care professional and can be subjective (e.g. opinion) orobjective (e.g. measurable by a test or diagnostic method).

In another embodiment, any of the above methods of treatment comprisesthe further step of co-administering to said patient one or more secondtherapeutic agents. The choice of second therapeutic agent may be madefrom any second therapeutic agent known to be useful forco-administration with pazopanib. The choice of second therapeutic agentis also dependent upon the particular disease or condition to betreated. Examples of second therapeutic agents that may be employed inthe methods of this invention are those set forth above for use incombination compositions comprising a compound of this invention and asecond therapeutic agent.

In particular, the combination therapies of this invention includeco-administering a compound of Formula I and a second therapeutic agentfor treatment of the following conditions: breast cancer (lapatinib),colorectal cancer (FOLFOX6 [fluorouracil, oxaliplatin, leucovorin],CapeOx [capecitabine, oxaliplatin]), solid tumor cancer (lapatinib,paclitaxel, carboplatin), malignant glioma (lapatinib), and cervicalcancer (lapatinib).

The term “co-administered” as used herein means that the secondtherapeutic agent may be administered together with a compound of thisinvention as part of a single dosage form (such as a composition of thisinvention comprising a compound of the invention and an secondtherapeutic agent as described above) or as separate, multiple dosageforms. Alternatively, the additional agent may be administered prior to,consecutively with, or following the administration of a compound ofthis invention. In such combination therapy treatment, both thecompounds of this invention and the second therapeutic agent(s) areadministered by conventional methods. The administration of acomposition of this invention, comprising both a compound of theinvention and a second therapeutic agent, to a patient does not precludethe separate administration of that same therapeutic agent, any othersecond therapeutic agent or any compound of this invention to saidpatient at another time during a course of treatment.

Effective amounts of these second therapeutic agents are well known tothose skilled in the art and guidance for dosing may be found in patentsand published patent applications referenced herein, as well as in Wellset al, eds., Pharmacotherapy Handbook, 2nd Edition. Appleton and Lange,Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000),and other medical texts. However, it is well within the skilledartisan's purview to determine the second therapeutic agent's optimaleffective-amount range.

In one embodiment of the invention, where a second therapeutic agent isadministered to a subject, the effective amount of the compound of thisinvention is less than its effective amount would be where the secondtherapeutic agent is not administered. In another embodiment, theeffective amount of the second therapeutic agent is less than itseffective amount would be where the compound of this invention is notadministered. In this way, undesired side effects associated with highdoses of either agent may be minimized. Other potential advantages(including without limitation improved dosing regimens and/or reduceddrug cost) will be apparent to those of skill in the art.

In yet another aspect, the invention provides the use of a compound ofFormula I alone or together with one or more of the above-describedsecond therapeutic agents in the manufacture of a medicament, either asa single composition or as separate dosage forms, for treatment orprevention in a patient of a disease, disorder or symptom set forthabove. Another aspect of the invention is a compound of Formula I orpharmaceutically acceptable salt thereof, or a composition comprising acompound of Formula I or pharmaceutically acceptable salt thereof, foruse in the treatment or prevention in a patient of a disease, disorderor symptom thereof delineated herein.

In one aspect, the compound of Formula I or pharmaceutically acceptablesalt thereof, or a composition comprising a compound of Formula I orpharmaceutically acceptable salt thereof is for use in treating adisease of condition selected from renal cell carcinoma, breast cancer,cervical cancer, non-small cell lung cancer, ovarian cancer, fallopiantube cancer, peritoneal cancer, prostate cancer, rhinopharyngeal cancer,solid tumor cancer, bladder cancer, urethral cancer, multiformeglioblastoma, malignant glioma, pleural mesothelioma, multiple myeloma,neuroendocrine cancer, sarcoma, colorectal cancer, liver cancer, maculardegeneration and psoriasis.

In another aspect, the compound of Formula I or pharmaceuticallyacceptable salt thereof, or a composition comprising a compound ofFormula I or pharmaceutically acceptable salt thereof is used inconjunction with a second therapeutic agent useful in the treatment ofcancer, ocular neovascular disorders, or psoriasis.

In another aspect, the compound of Formula I or pharmaceuticallyacceptable salt thereof, or a composition comprising a compound ofFormula I or pharmaceutically acceptable salt thereof is for use intreating breast cancer, malignant glioma, cervical cancer and solidtumor cancer; and the compound or composition is used in conjunctionwith lapatinib.

In another aspect, the compound of Formula I or pharmaceuticallyacceptable salt thereof, or a composition comprising a compound ofFormula I or pharmaceutically acceptable salt thereof is for use intreating colorectal cancer; and the compound or composition is used inconjunction with a second therapeutic agent selected from a combinationof fluorouracil, oxaliplatin, and leucovorin; and a combination ofcapecitabine and oxaliplatin.

In another aspect, the compound of Formula I or pharmaceuticallyacceptable salt thereof, or a composition comprising a compound ofFormula I or pharmaceutically acceptable salt thereof is for use intreating a solid tumor cancer; and the compound or composition is usedin conjunction with a second therapeutic agent selected from paclitaxel,or carhoplatin.

The term “used in conjunction with” as used herein means administeredsimultaneously with, or administered within 24 hours of the subjectcompound or composition.

Pharmaceutical Kits

The present invention also provides kits for use to treat renal cellcarcinoma, breast cancer, cervical cancer, non-small cell lung cancer,ovarian cancer, fallopian tube cancer, peritoneal cancer, prostatecancer, rhinopharyngeal cancer, solid tumor cancer, bladder cancer,urethral cancer, multiforme glioblastoma, malignant glioma, pleuralmesothelioma, multiple myeloma, neuroendocrine cancer, sarcoma,colorectal cancer, liver cancer, macular degeneration and psoriasis.These kits comprise (a) a pharmaceutical composition comprising acompound of Formula I or a salt thereof, wherein said pharmaceuticalcomposition is in a container; and (b) instructions describing a methodof using the pharmaceutical composition to treat renal cell carcinoma,breast cancer, cervical cancer, non-small cell lung cancer, ovariancancer, fallopian tube cancer, peritoneal cancer, prostate cancer,rhinopharyngeal cancer, solid tumor cancer, bladder cancer, urethralcancer, multiforme glioblastoma, malignant glioma, pleural mesothelioma,multiple myeloma, neuroendocrine cancer, sarcoma, colorectal cancer,liver cancer, macular degeneration and psoriasis.

The container may be any vessel or other sealed or sealable apparatusthat can hold said pharmaceutical composition. Examples include bottles,ampules, divided or multi-chambered holders bottles, wherein eachdivision or chamber comprises a single dose of said composition, adivided foil packet wherein each division comprises a single close ofsaid composition, or a dispenser that dispenses single doses of saidcomposition. The container can be in any conventional shape or form asknown in the art which is made of a pharmaceutically acceptablematerial, for example a paper or cardboard box, a glass or plasticbottle or jar, a re-sealable bag (for example, to hold a “refill” oftablets for placement into a different container), or a blister packwith individual doses for pressing out of the pack according to atherapeutic schedule. The container employed can depend on the exactdosage form involved, for example a conventional cardboard box would notgenerally be used to hold a liquid suspension. It is feasible that morethan one container can be used together in a single package to market asingle dosage form. For example, tablets may be contained in a bottle,which is in turn contained within a box. In one embodiment, thecontainer is a blister pack.

The kits of this invention may also comprise a device to administer orto measure out a unit dose of the pharmaceutical composition. Suchdevice may include an inhaler if said composition is an inhalablecomposition; a syringe and needle if said composition is an injectablecomposition; a syringe, spoon, pump, or a vessel with or without volumemarkings if said composition is an oral liquid composition; or any othermeasuring or delivery device appropriate to the dosage formulation ofthe composition present in the kit.

In an embodiment of the kits of this invention, the compositioncomprising the second therapeutic agent may be in a vessel or containerthat is separate from the vessel containing the composition comprising acompound of Formula I.

Example 1 Evaluation of Metabolic Stability

Microsomal Assay: Human liver microsomes (20 mg/mL) are obtained fromXenotech. LLC (Lenexa, Kans.). β-nicotinamide adenine dinucleotidephosphate, reduced form (NADPH), magnesium chloride (MgCl₂), anddimethyl sulfoxide (DMSO) are purchased from Sigma-Aldrich.

Determination of Metabolic Stability: 7.5 mM stock solutions of testcompounds are prepared in DMSO. The 7.5 mM stock solutions are dilutedto 12.5-50 μM in acetonitrile (ACN). The 20 mg/mL human liver microsomesare diluted to 0.625 mg/mL in 0.1 M potassium phosphate buffer, pH 7.4,containing 3 mM MgCl₂. The diluted microsomes are added to wells of a96-well deep-well polypropylene plate in triplicate. A 10 μL aliquot ofthe 12.5-50 μM test compound is added to the microsomes and the mixtureis pre-warmed for 10 minutes. Reactions are initiated by addition ofpre-warmed NADPH solution. The final reaction volume is 0.5 mL andcontains 0.5 mg/mL human liver microsomes, 0.25-1.0 μM test compound,and 2 mM NADPH in 0.1 M potassium phosphate buffer, pH 7.4, and 3 mMMgCl₂. The reaction mixtures are incubated at 37° C., and 50 μL aliquotsare removed at 0, 5, 10, 20, and 30 minutes and added to shallow-well96-well plates which contain 50 μL of ice-cold ACN with internalstandard to stop the reactions. The plates are stored at 4° C. for 20minutes after which 100 μL of water is added to the wells of the platebefore centrifugation to pellet precipitated proteins. Supernatants aretransferred to another 96-well plate and analyzed for amounts of parentremaining by LC-MS/MS using an Applied Bio-systems API 4000 massspectrometer. The same procedure is followed for pazopanib and thepositive control, 7-ethoxycoumarin (1 μM). Testing is done intriplicate.

Data analysis: The in vitro t_(1/2)s for test compounds are calculatedfrom the slopes of the linear regression of % parent remaining (In) vsincubation time relationship.

in vitro t _(1/2)=0.693/k

k=−[slope of linear regression of % parent remaining(ln)vs incubationtime]

Data analysis is performed using Microsoft Excel Software.

Without further description, it is believed that one of ordinary skillin the art can, using the preceding description and the illustrativeexamples, make and utilize the compounds of the present invention andpractice the claimed methods. It should be understood that the foregoingdiscussion and examples merely present a detailed description of certainpreferred embodiments. It will be apparent to those of ordinary skill inthe art that various modifications and equivalents can be made withoutdeparting from the spirit and scope of the invention. All the patents,journal articles and other documents discussed or cited above are hereinincorporated by reference.

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: each Y isindependently selected from hydrogen and deuterium; each R isindependently selected from CH₃, CH₂D, CHD₂ and CD₃; and when each R isCH₃, at least one Y is deuterium.
 2. The compound of claim 1, whereineach R is independently selected from CH₃ and CD₃.
 3. The compound ofclaim 2, wherein R¹ is CD₃.
 4. The compound of claim 3, wherein Y¹, Y²and Y³ are the same.
 5. The compound of claim 4, wherein Y⁶, Y⁷ and Y⁸are the same.
 6. The compound of claim 5, wherein Y⁵ is deuterium. 7.The compound of claim 2, wherein Y¹, Y² and Y³ are simultaneouslydeuterium.
 8. The compound of claim 1, selected from any one of thecompounds set forth in the table below: Compound Y¹ R¹ Y² Y³ Y⁴ Y⁵ Y⁶ Y⁷R² R³ Y⁸ R⁴ 100 D CD₃ D D D D D D CD₃ CD₃ D CD₃ 101 H CD₃ H H D D D DCD₃ CD₃ D CD₃ 102 D CD₃ D D H D D D CD₃ CD₃ D CD₃ 103 D CD₃ D D D H D DCD₃ CD₃ D CD₃ 104 D CD₃ D D H H D D CD₃ CD₃ D CD₃ 105 D CD₃ D D D D H HCD₃ CD₃ H CD₃ 106 H CD₃ H H H H H H CD₃ CD₃ H CD₃ 107 H CH₃ H H H H H HCH₃ CD₃ H CD₃ 108 H CH₃ H H H H H H CH₃ CH₃ H CD₃ 109 H CH₃ H H H H H HCH₃ CD₃ H CH₃ 110 H CH₃ H H H H H H CD₃ CD₃ H CD₃ 111 H CD₃ H H H H H HCH₃ CD₃ H CD₃


9. The compound of claim 8, wherein any atom not designated as deuteriumis present at its natural isotopic abundance.
 10. A pyrogen-freepharmaceutical composition comprising a compound of claim 1 orpharmaceutically acceptable salt thereof and an acceptable carrier. 11.The composition of claim 10 additionally comprising a second therapeuticagent useful in the treatment or prevention of a disease or conditionselected from cancer; ocular neovascular disorders; and psoriasis. 12.The composition of claim 11, wherein the second therapeutic agent isselected from lapatinib; a combination of fluorouracil, oxaliplatin, andleucovorin; a combination of capecitabine and oxaliplatin; paclitaxel;and carboplatin.
 13. The compound of claim 11 for use in inhibiting theactivity of one or more of a VEGF-1, VEGF-2, or VEGF-3 receptor in acell.
 14. The compound of claim 11 for use in treating a disease orcondition selected from cancer; ocular neovascular disorders; andpsoriasis.
 15. The compound or composition of claim 14, wherein thedisease or condition is selected from renal cell carcinoma, breastcancer, cervical cancer, non-small cell lung cancer, ovarian cancer,fallopian tube cancer, peritoneal cancer, prostate cancer,rhinopharyngeal cancer, solid tumor cancer, bladder cancer, urethralcancer, multiforme glioblastoma, malignant glioma, pleural mesothelioma,multiple myeloma, neuroendocrine cancer, sarcoma, colorectal cancer,liver cancer, macular degeneration and psoriasis.
 16. The compound orcomposition of claim 15, wherein the composition is used in conjunctionwith a second therapeutic agent useful in the treatment of cancer,ocular neovascular disorders, or psoriasis.
 17. The compound orcomposition of claim 16, wherein: a. the disease or condition isselected from breast cancer, malignant glioma, cervical cancer and solidtumor cancer; and the compound or composition is used in conjunctionwith lapatinib; b. the disease or condition is colorectal cancer; andthe compound or composition is used in conjunction with a secondtherapeutic agent selected from a combination of fluorouracil,oxaliplatin, and leucovorin; and a combination of capecitabine andoxaliplatin; or c. the disease or condition is a solid tumor cancer; andthe compound or composition is used in conjunction with a secondtherapeutic agent selected from paclitaxel, or carboplatin.